Oral Enzyme Therapy in the Treatment of Ankle Joint
Distortions
(MU-692423)
Principal Investigator:
Hanns-Dietrich Rahn, M.D. Oral Enzyme Therapy in the Treatment of
Ankle Joint Distortions (MU-692423). Efficacy and Safety. Study No.:
MU-692423. Randomised,
double-blind, controlled clinical trial with two parallel groups
Phlogenzym® vs. enzyme preparation without rutoside.
Integrated biometric-medical final report according to FDA and CPMP
guidelines. Schwalbacherstrasse 38, D-65183 Wiesbaden, Germany.
Evaluation and report by: idv - Datenanalyse/Versuchsplanung, Albert
Schwenck, Senior Manager, Wessobrunnerstrasse 6, D-82131 Gauting,
Germany. Head of biometrical evaluation: idv - Datenanalyse/Versuchsplanung,
Dr. Volker W. Rahlfs, C. Stat. Certificate "Biometry in Medicine"
(GMDS), Wessobrunnerstrasse 6, D-82131 Gauting, Germany. Translation
by: Pharma Script, Kathi-Kobus-Steig 1, D-82515 Wolfratshausen,
Germany
Summary and Discussion
In this study the effect of an enzyme preparation with rutosid in
patients suffering from an ankle joint distortion was to be
demonstrated. The efficacy of the enzyme preparation containing
rutosid, Phlogenzym, was compared to the efficacy of a preparation
containing only enzymes without rutosid. The randomized, clinical
double-blind study phase III with two parallel groups was conducted
in accordance with GCP guidelines. The duration of the therapy per
patient was 10 days. The first patient was admitted on 11-23-1992
and the last patient on 11-03-1993. The last patient completed the
study on 11-12-1993. All patients completed the study according to
protocol.
All in all 60 patients were admitted into the study. According to
the randomization the 60 patients were devided into two groups of 30
patients. One group received Phlogenzym®, the other
enzyme dragees without rutosid. The daily dose in both groups was 3
x 2 dragees in a period of 10 days. The compliance was checked after
the end of therapy by counting the unused enzyme dragees. All 60
patients could be considered for the evaluation of the efficacy and
tolerance. The main criteria for the efficacy was the regression of
swelling, defined as the difference between the circumference of the
traumatic and intact ankle joint (in cm).
Secondary criteria for the efficacy were the index of pain (sum
score of pain at rest and pain in movement), joint effusion, pain at
rest and pain in movement (all three criteria were judged using a
4-step scale), flexibility (the difference of the traumatic and
intact ankle joint in degrees), expenditure of analgesics, lost days
of work and training and the global assessment of the efficacy by
the physician and the patients (5-step scale from 1 = excellent to 5
= poor).
A two tailed testing on the difference was conducted. The testing of
the difference between the two treatment groups at the different
examination times was done with the Wilcoxon-Mann-Whitney U-test.
The Mann-Whitney statistic and the standardized difference were used
as a measure for the efficacy in the differences between the groups.
The following applies in the assessment for the two superiority
measures:
|
Difference |
Mann-Whitney statistic |
Standardized difference |
|
no |
0.50 |
0.0 |
|
small |
0.56 |
0.2 |
|
medium |
0.64 |
0.5 |
|
big |
0.71 |
0.8 |
To determine the
mean difference and the area of confidence as well as the
standardized difference and its area of confidence the t-test was
done. In addition, an ANCOVA was carried out to confirm the test
results and to check the potential influences such as, for example,
the Lorenz index.
The expenditure of analgesics and the frequency of adverse events
were compared with the Fisher's test.
Results
Main Criteria
In both treatment groups the swelling at the individual
examinations compared to pre-Rx had decreased, more so in the
Phlogenzym group than in the enzyme without rutosid group. On day 4
the decrease compared to pre-Rx was 0.6 cm in the Phlogenzym group,
0.4 cm in the enzyme without rutosid group, on day 7 it was 1.1 cm
in the Phlogenzym group, 0.7 cm in the enzyme without rutosid group
and on day 10 the decrease was 1.7 cm in the Phlogenzym group and
1.2 in the enzyme without rutosid group.
On day 7 a great difference in favor of Phlogenzym® was
evident, P = 0.0002, Mann-Whitney statistic P(X<Y) + 0.5 P(X=Y) =
0.8. But also on days 4 (P = 0.004, Mann-Whitney statistic P(X<Y) +
0.5 P(X=Y) = 0.71 ) and 10 (P = 0.004, Mann-Whitney statistic P(X<Y)
+ 0.5 P(X=Y) = 0.72) great differences in favor of Phlogenzym®
were noticed.
In the change compared to pre-Rx the standardized difference showed
a great difference (0.9) in favor of Phlogenzym®, on day
4 a medium difference (0.5) and on day 10 a medium to great
difference (0.7).
Using the scatter diagram it could be observed that a proportionate
improvement by a constant value took place in both groups. To secure
the results the appropriate co-variance analysis was employed.
The differences of the main criteria on the observation scale does
not appear too big (day 7: t-test 0.41, ANCOVA: 0.35). The
standardized difference on the other hand is considerable: the known
value of the Mann-Whitney on the difference shows a great difference
(0.71 = great) with 0.78, the standardized difference is great with
a value of 0.9 (0.8 = great according to COHEN).
Secondary Criteria of the Efficacy
Index of Pain
Concerning the reduction of the index of pain compared to pre-Rx
a medium to big difference in favor of Phlogenzym®
existed on day 7, Mann-Whitney statistic = 0.67, standardized
difference =0.63; P = 0.0166. The same trend as in the swelling is
found in the index of pain, although it was not as well developed as
in the swelling.
Joint Effusion, Pain at Rest and Pain in Motion
There was no significant difference between the two groups at
any point of time concerning the joint effusion; regarding the pain
at rest and pain in movement, small differences in favor of
Phlogenzym® were seen on days 7 and 10 (P(X<Y)+0.5P(X=Y)
for the pain at rest = 0.56 and = 0.58; for the pain in movement =
0.57 and 0.56).
Flexibility of the Ankle Joint
For the flexibility of the ankle joint the difference between
traumatic and intact ankle joint was evaluated. The decrease in
degrees on day 7 on average was 17.8 in the Phlogenzym group and
11.2 in the enzyme group. The improvement of the flexibility
resembles the trend of the swelling and the index of pain. This
means that an increase in flexibility takes place in both treatment
groups but the Phlogenzym group displays a more rapid increase of
flexibility than the enzyme without rutosid group does.
From day 4 on great differences in favor of Phlogenzym®
could be seen in the change of the flexibility compared to pre-Rx
(P-value on day 4 = 0.0056, on day 7 = 0.0029, on day 10 = 0.0033;
P(X<Y)+0.5P(X=Y) on day 4 = 0.71, on day 7 = 0.72, on day 10 =
0.72).
Use of Analgesics
Regarding the use of analgesics no difference between the groups
could be detected (P = 0.612).
Days of Disability
The average difference in days of work lost was 1.5 days in
favor of Phlogenzym® (confidence interval: -0.29 to
3.36). The difference in the t-test was not significant, P = 0.0979.
The standardized difference shows a small to medium difference of
0.4. In the days of training lost a medium difference of 1.8 days
(confidence interval: -0.51 to 3.81) in favor of Phlogenzym®
was found, but there was no significance in the t-test, P = 0.0688.
The standardized difference shows a medium difference of 0.5 in
favor of Phlogenzym®.
For the patients who lost days of work !and! training a medium
difference of 2.0 days (confidence interval: 0.49 to 3.50) resulted
in the days of work lost. The p-value was 0.010. The standardized
difference shows a great difference of 0.8 in favor of Phlogenzym®.
In the days of training lost a medium difference of 2.2 days
(confidence interval: 0.84 to 3.61 ) and a p-value of 0.002 was
discovered. The standardized difference shows a great difference of
0.9 in favor of Phlogenzym®.
This leads to the assumption that 1.5 or even 2.0 lost days of work
are saved and 1.8 to 2.2 lost days of training can be regained which
is of economical significance. But this statement is burdened with
uncertainty as becomes evident when considering the great range of
the area of confidence. Only after further studies with a greater
number of cases can a precise statement be made.
Global Assessment of the Efficacy by the Physician and the
Patient
In the global assessment of the efficacy small to medium
differences were found in favor of Phlogenzym®
(P(X<Y)+0.5(X=Y) = 0.61 ). The global asessment, similar to the
index of pain, does not discriminate the groups as much as the
measurements of the swelling and the flexibility do, which means
that the values are not as responsive as the measurements of the
swelling and flexibility. Physician and patient agreed about the
assessment of the efficacy in 21 (70%) of 30 cases in the Phlogenzym
group and in 15 (50%) of 30 cases in the enzyme without rutosid
group.